The application of adenovirus vector (AdV) as a gene transfer vehicle for human gene therapy has been limited by both humoral and cellular immune responses of the host to the vector as well as the transgene. Although the performance of AdV can be improved by crippling adenoviral gene expression or deleting more key genes, several key obstacles remain. Current evidence suggests that the humoral response precludes the treatment of individuals who are immunocompetent and who have been previously exposed to the virus, either accidentally or by deliberate immunization. This proposal suggests a new approach to bypass humoral immunity, based on modified vectors and new polymers. Polyethyleneglycol (PEG) modification of therapeutic proteins has been a well established strategy to reduce their immunogenicity and enhance activity. Masking viral particles with PEG has the potential to reduce their immunogenicity and clearance by macrophages and may allow adenoviral vectors to be used in individuals who have already been exposed to adenovirus and have neutralizing antibody in their plasma. In order to carry out the derivatization of the virus with PEG, we propose to alter the capsid proteins to facilitate PEG addition. The PEG-masked AdV will be used and compared to the unmodified AdV in gene transfer experiments in mice immunized with wild type Ad prior to AdV instillation. Finally, the utility of the approach will be tested by measuring the sustained expression of human growth hormone in the circulation of mice by repeatitive injection of the PEG-masked recombinant AdV capable of expressing this potentially therapeutic protein.